Drugs that have been orally administered quickly pass through the esophagus to reach the stomach. The stomach lining is made from the three layers of mucosa, tunica muscularis, and tunica serosa. However, in contrast to the small intestine, its effective surface area of absorption is small and therefore, with the exception of some drugs, the stomach lining plays a small role as an absorption site. On the other hand, the human small intestine consists of the duodenum, jejunum, and ileum and is the longest part of the gastrointestinal system and the surface area that is effective in absorption is large. Therefore, it is the site that is suitable for absorption of most drugs. However, epithelial cells, which have a plasma membrane made from a lipid double layer, cover very closely the surface of the gastrointestinal mucosa site and therefore, absorption is greatly restricted in the case of drugs that are very water-soluble and polymer drugs. Moreover, in addition to the gastrointestinal mucosa, the mucous layers that normally cover the gastrointestinal mucosa become a barrier that inhibits gastrointestinal absorption of a biologically active peptide, such as vasopressin and the like. Consequently, drugs that have been orally administered are first absorbed in vivo after passing through the two barriers of the mucous layers that cover the surface of the above-mentioned gastrointestinal mucosa and the mucosa. A biologically active peptide are decomposed by secreted digestive enzymes present in the gastrointestinal mucosa and/or mucous layers and/or mucus distributed over the mucosa before they reach the absorption site and therefore, in addition to the above-mentioned barriers, digestive enzymes form yet another barrier.
Technology with which a biologically active peptide are absorbed from the digestive tract without being decomposed has been an objective for years, but has yet to be established. The following methods are known as technology whereby absorption by oral administration of a biologically active peptide is accelerated:
One of these technologies is the method whereby, for instance, bile acid salts (WO 9606635), which have surfactant activity, amphoteric surfactants such as o-acyl-L-carnitines having acyl groups with 8 to 18 carbons (U.S. Pat. No. 4,537,772), and the like, or anionic surfactants such as sodium lauryl sulfate (SLS), and the like are used, or the method whereby bile acid salts and SLS are concomitantly used (Pharm Res., 7, No. 9, Suppl., S157, 1990). By means of such methods, fluidity of the cell membrane is increased and therefore, absorption of very water-soluble substances is accelerated. However, they are not used for practical purposes because of problems with cytotoxicity (Journal of Controlled Release, 29, 253, 1994).
The method is also given whereby chelation agents such as EDTA (J. Pharm. Pharmacol., 51, No. 11, 1241-50, 1999), EGTA, and the like, or enzyme inhibitors, such as trypsin inhibitors (J. Pharm. Pharmacol., 50, No. 8, 913-20, 1998), and the like, are used. This is a method whereby intercellular space is loosened by withdrawing calcium ions to accelerate membrane permeation by high polymer substances. However, if the concentration is not relatively high, absorption effects are not realized at the biological pH (approximately neutral), and there are also reports of mucous dysfunction by withdrawing calcium ions.
The method is also given whereby insulin is modified by caproic acid (J. Pharm. Sci., 84, No. 6, pp. 682-687, 1995). By means of this method, various a biologically active peptide and higher fatty acids or their esters are modified by synthesis. Therefore, it is a method that is accompanied by a separate complex process of synthesis. Moreover, there is a reduction in peptide activity as a result of modification.
There is also the method whereby polyacrylic acid gel base, such as polycarbophyl, Carbopol, or (meth)acrylic acid-maleic acid copolymer (U.S. Pat. No. 6,004,575), and the like, or polymer substances, such as chitosan, and the like, is used. This method is intended to accelerate absorption of a biologically active peptide by loosening intercellular space. It asserts that polyacrylic acids gel base can inhibit decomposition of a biologically active peptide by a digestive enzyme as a result of forming a chelate with metal ions (Int. J. Pharm., 141, pp. 39-52, 1996). However, this base is very viscous even though the polymer itself is at a relatively low concentration, and therefore, practical application of this base is said to be difficult. Therefore, although the (meth)acrylic acid-maleic acid copolymer in U.S. Pat. No. 6,004,575 is given as one that reduces viscosity of polyacrylic acid gel bases, it appears that because structurally, this polymer has many carboxyl groups, the use of this polymer will lead to an increase in viscosity of the mucous layers distributed over in gastrointestinal mucosa.
It is reported that chitosan accelerates absorption by loosening intercellular space (Int. J. Pharm., 185, 1, pp. 73-82, 1999). However, because chitosan does not have the ability to inhibit enzymes that decompose a biologically active peptide (Int. J. Pharm., 159, pp. 243-253, 1997), or interact with the mucous layers distributed over the gastrointestinal mucosa to reduce substance permeability of the mucous layers (Eur. J. Pharm. Sci., 8, No. 4, 335-43, 1999), it does not appear that sufficient absorption will be obtained even if chitosan is used.
The following methods are further known as technologies whereby aminoalkyl methacrylate copolymer E is used in order to improve absorption by oral administration of drugs:
An invention is described in specific terms in International Publication Pamphlet WO 00/43041A1 relating to a pharmaceutical composition for oral use with improved absorption comprising a drug that is difficult to absorb because it forms a complex with bile acids, which is difficult to absorb, and aminoalkyl methacrylate copolymer E. Moreover, an invention is also disclosed in the same pamphlet relating to a pharmaceutical composition obtained by dissolution or suspension of aminoalkyl methacrylate copolymer E and surfactant in a solvent and spray drying this solution. Nevertheless, there is no disclosure or indication that the aminoalkyl methacrylate copolymer E that is the active ingredient of the present invention has three effects, (1) the ability to inhibit (prevent) decomposition of biologically active peptide by digestive enzymes in the gastrointestinal mucosa and/or mucous layers distributed over this mucosa, (2) the ability to reduce viscosity of the gastrointestinal mucosa and/or mucous layers distributed over this mucosa (the ability to improve permeability of a biologically active peptide in the mucous layers), and (3) the ability to improve permeability of a biologically active peptide in the gastrointestinal mucosa.
An invention relating to a pharmaceutical preparation in powder form for permucosal administration, which comprises polymer drug, aminoalkyl methacrylate copolymer E as cationic polymer, and the like, is disclosed in International Publication Pamphlet WO 00/02574A1. Nevertheless, only a pharmaceutical preparation for pernasal administration is produced in the examples and only the results relating to pernasal mucosa absorption are confirmed, and there is never any disclosure of the effects of aminoalkyl methacrylate copolymer E on absorption of a biologically active peptide by other mucous membranes, particularly absorption of a biologically active peptide when used as a pharmaceutical preparation for oral administration.
On the other hand, aminoalkyl methacrylate copolymer E is a copolymer of methyl methacrylate, butyl methacrylate, and dimethylaminoethyl methacrylate developed by Röhm, and is a polymer substance marketed under the brand name Eudragit™ E100 or Eudragit™ EPO (both by Röhm GmbH). Its average molecular weight is 150,000 (Pharmaceutical Additives Standard, p. 76-77, 1998, Yakuji Nippo Co., Ltd.; Handbook of Pharmaceutical Excipients, Second Edition, p. 362-366, 1994, American Pharmaceutical Association, Washington and the Pharmaceutical Press, London).
Aminoalkyl methacrylate copolymer E is one type of well-known film coating base that is commonly used for masking the bitter taste and color and moisture-proofing, and the like, of caplets and granules, which (1) is quickly dissolved by gastric juices and (2) dissolves in buffers with a pH of 5.0 or lower, but with which the film inflates in buffers with a pH of 5.0 or higher, and the like. Aminoalkyl methacrylate copolymer E has been used in the past for the purpose of masking the bitter taste and color and moisture-proofing drugs, as well as solubilization, and the like, of drugs.
Consequently, there is a need today to present technology with which a biologically active peptide are absorbed without being decomposed in the digestive tract.